In order to develop a model for a depression-like syndrome in mice, we subjected male C57BL/6 mice to a 4-week-long chronic stress procedure, consisting of rat exposure, restraint stress, and tail suspension. This protocol resulted in a strong decrease in sucrose preference, a putative indicator of anhedonia in rodents. Interestingly, predisposition for stress-induced anhedonia was indicated by submissive behavior in a resident–intruder test. In contrast, most mice with nonsubmissive behavior did not develop a decrease in sucrose preference and were regarded as nonanhedonic. These animals were used as an internal control for stress-induced behavioral features not associated with the anhedonic state, since they were exposed to the same stressors as the anhedonic mice. Using a battery of behavioral tests after termination of the stress procedure, we found that anhedonia, but not chronic stress per se, is associated with key analogues of depressive symptoms, such as increased floating during forced swimming and decreased exploration of novelty. On the other hand, increased anxiety, altered locomotor activity, and loss of body weight were consequences of chronic stress, which occurred independently from anhedonia. Thus, behavioral correlates of stress-induced anhedonia and of chronic stress alone can be separated in the present model.

The immediate early gene c-fosis part of the activator protein-1 transcription factor and has been postulated to participate in the molecular mechanisms of learning and memory. To test this hypothesisin vivo, we generated mice with a nervous system-specific c-fosknock-out using the Cre-loxP system. Adult mice lacking c-Fos in the CNS (c-fos^ΔCNS) showed normal general and emotional behavior but were specifically impaired in hippocampus-dependent spatial and associative learning tasks. These learning deficits correlated with a reduction of long-term potentiation (LTP) in hippocampal CA3-CA1 synapses. The magnitude of LTP was restored by a repeated tetanization procedure, suggesting impaired LTP induction in c-fos^ΔCNSmice. This rescue was blocked by a selective inhibitor of NR2B-type NMDA receptors. This blockade was compensated in wild-type mice by NR2A-type NMDA receptor-activated signaling pathways, thus indicating that these pathways are compromised in c-fos^ΔCNSmice. In summary, our data suggest a role for c-Fos in hippocampus-dependent learning and memory as well as in NMDA receptor-dependent LTP formation.

Chronic stress is broadly used to model anxiety and depression. However, in chronic stress models, anxiety- and depression-like behaviors might be masked by unspecific effects of stress. We tested whether chronic stress in mice can induce unspecific changes in locomotion, and whether these changes interfere with the measurement of anxiety and forced-swimming behaviors. Also, we studied these latter behaviors in relation to the duration of stress, the lighting conditions during testing, and after the injection of diazepam. We employed a 4-week chronic stress paradigm, adopted from a model of stress-induced anhedonia and a 1-week subchronic stress, both consisting of rat exposure, restraint stress and tail suspension. Chronically stressed mice, tested under bright and moderate illumination, exhibited ‘anxiolytic-like’ behavior along with prolonged swimming and hyperactivity. These behaviors were not detectable under weak illumination or after the injection of diazepam (0.25 mg/kg). Instead, normal locomotion, increased anxiety and inhibited swimming were revealed under these conditions. Thus, chronic stress can induce hyperlocomotion in mice, which is triggered by acute stressors such as light, and interferes with the evaluation of anxiety and forced swimming. One week of stress did not change locomotion and forced swimming, and increased anxiety irrespective of illumination applied during testing. Our data can possibly explain previously reported contradictions in the behavioral testing of mice with chronic stress models of anxiety and depression.